Notwithstanding a statutory deadline of two years after the enactment of the 2013 Drug Supply Chain Security Act (“DSCSA”), FDA has finally published a draft guidance document on waivers, exceptions, and exemptions (“WEE”) from certain requirements of FDCA Section 582.  Since late November 2013, the pharmaceutical drug supply chain and FDA have been inching towards implementation of the DSCSA’s multi-layered requirements aimed at enhancing drug supply chain security.  Pursuant to Section 582, trading partners in the pharmaceutical distribution supply chain must implement over a period of time certain tracking, tracing, and product identification requirements.  Section 582(a)(3) contains a “waiver, exception, and exemption” provision permitting under certain circumstances trading partners to apply to FDA for a WEE from what can be onerous compliance provisions (and FDA can initiate waivers and exemptions on its own).  Although lacking in much detail on what types of products or under what conditions trading partners may receive the requested WEEs, at least there is a process in place to attempt to obtain one before the effective date of FDA’s product identification (i.e., serialization) requirements go into effect later this year.

The short draft guidance document describes generally that WEE requests should be in writing (either paper or electronic), and submitted by a trading partner or stakeholder to the product correspondence file associated with the particular application for CBER-regulated products. For all other WEE requests, including CDER-regulated products, such requests should be submitted to CDER as set forth in the draft guidance. (An appendix to the guidance contains FDA contact information for submissions.)

The draft guidance details what a requester should include in each WEE request:

• The name, telephone number, and email address of an individual who FDA can contact about matters relating to the proposed waiver, exception, or exemption
• The identity of the trading partner(s) that would be covered by the proposed waiver, exception, or exemption
• A description of the activities and/or products (including the national drug code number) for which the proposed waiver, exception, or exemption is being sought
• The requested effective period of the waiver, exception, or exemption
• The requirements of FDC Act Section 582 to which the proposed waiver, exception, or exemption would apply
• A detailed statement of the reasons why FDA should grant the proposed waiver, exception, or exemption, including pertinent supporting documentation

FDA will also require the applicant to complete an attestation concerning the veracity of the information pursuant to 18 U. S.C. § 1001. FDA states that it will review the requests, and determine whether the request is sufficient.   Along with considering risks to the security of the supply chain, the Agency will review a request with its subject matter experts, and determine as follows:

• Whether a waiver request concerning the Section 582 requirements identified in the request is warranted because compliance with it would result in undue economic hardship or is appropriate with emergency medical reasons.
• Whether a request for an exception to Section 582’s requirements relating to product identifier is warranted because the product package is too small or otherwise unable to accommodate a label with sufficient space to hold all the required information
• Exempting products and/or transactions identified in the request from Section 582 requirements is appropriate to maintain public health “or is otherwise appropriate.”

Furthermore, FDA states that the Agency may initiate its own WEE, or may grant a request of limited duration. To minimize risks to the supply chain, FDA expects to limit the duration of WEEs that it grants. FDA will notify requesters in writing of its determinations and may post such information on its website as well, consistent with laws concerning disclosure of such information.

FDA expects to review or reevaluate requests biennially. It will renew such WEEs “as applicable” and determine whether there has been a material change in circumstances affecting the necessity of the WEE. FDA specifically notes as an example of requesting additional information: a situation where a recipient received an “undue economic hardship” waiver may be asked to submit financial information so FDA may determine whether financial circumstances changed.

With respect to “material changes” after a request is granted (i.e., an increase in package size such that the package would be able to accommodate a product identifier), FDA expects the requestor to notify FDA of the material change, and not await FDA’s biennial review of the request. FDA also describes its proposed process for FDA-initiated exceptions and exemptions, stating it only intends to use these as necessary when an issue affects broad segments of a product market (i.e., a drug container is too small or unable to accommodate a label to bear information required under the DSCSA). These situations will seemingly be rare, as FDA states it will only initiate such exceptions and exceptions when necessary to protect the public health.

Late last month, CDER’s Office of Pharmaceutical Quality (OPQ) published a MAPP (Manual of Policies and Procedures #5310.3) outlining its policy for granting or denying expedited reviews of NDA and BLA Prior Approval Supplements (PAS) that involve chemistry, manufacturing and controls (CMC) changes overseen by OPQ.

Below are the pertinent highlights of the MAPP:

• An expedited review in the context of this MAPP, is FDA-speak for seeking to assess and act on the PAS prior to the Prescription Drug User Fee Act (PDUFA) goal date associated with that PAS;
• Normally, the sponsor is expected to make the request for expedited review, however, if the public need arises, OPQ may designate the CMC PAS for expedited review of its own initiative;
• OPQ will only consider requests for expedited review that clearly state the basis for the request;
• OPQ can designate a CMC PAS for expedited review at the time it receives the PAS or at any time thereafter. For instance, if OPQ receives a request for expedited review after the office has already processed the PAS, OPQ will consider the request and could still expedite the review of the PAS;
• OPQ will not consider a request for an expedited review that involves a facility that is subject to an OAI recommendation, unless an expedited review will help address a public health concern;
• OPQ will consider an expedited review request for a CMC PAS that falls into one of the following categories:
  • drug shortages;
  • special review programs such as the President’s Emergency Plan for AIDS Relief;
  • public health emergencies;
  • certain government purchasing programs;
  • statutory mandates or other legal requirements;
  • events that constitute extraordinary hardship on the applicant, such as a catastrophic event (eg, storm or fire damage), or the discontinuation of supply of an active ingredient or other material.

As it turns out, the categories for which OPQ will consider an expedited review request for a CMC PAS are not that dissimilar from the ones that the Office of Generic Drugs has previously indicated it will consider for expedited review of ANDAs, ANDA amendments, and ANDA supplements in its MAPP 5240.3, the most recent version of which was published on November 9, 2017. The only difference between the two MAPPs in that regard is that MAPP 5240.3 also includes the following categories, which are a function of the types of applications it reviews:

• submissions containing certain patent certifications and exclusivity statements;
• submissions for “sole source” drug products, i.e., “Submissions for drug products for which there is only one approved drug product listed in the Prescription Drug Product List (i.e., the “active section”) of the Orange Book and for which there are no blocking patents or exclusivities may receive a priority review, except when the approved drug product was approved pursuant to a suitability petition under section 505(j)(2)(C) of the Federal Food, Drug and Cosmetic Act.”

To summarize, the new MAPP 5310.3 for CMC PASs related to NDAs and BLAs is just a logical extension of the pre-existing MAPP 5240.3 for ANDAs, ANDA amendments and ANDA supplements. So, the next time your API supplier’s facility is knocked out by a torrential storm, you’ll know FDA’s position regarding the expedited review of your application or supplement!

On April 27, 2018 FDA released a draft guidance describing the regulatory approach and policy for multiple function device products. The draft guidance, Multiple Function Device Products: Policy and Considerations, is available here and has been issued in response to the 21st Century Cures Act section 3060(a) “Clarifying Medical Software Regulation.”

The term “function” is defined as “a distinct purpose of the product, which could be the intended use or a subset of the intended use of the product.” Draft Guidance at 4. The draft guidance is intended to clarify how FDA assesses the impact of functions that are not subject to FDA review when they are part of a multi-function product that includes at least one function that is subject to FDA review.

In short, the draft guidance indicates that FDA will not regulate functions of a multi-function product that do not meet the statutory device definition or are devices that are subject to an existing enforcement discretion policy. Also, though issued in relation to software functions, FDA states that they apply the same principles to the assessment of all multiple function products, not just those that contain software.

During review of premarket applications, FDA will assess the impact of “other functions” on a device function-under-review without reviewing the specifics of the other functions’ design and performance not related to the device function-under-review. In assessing the impact that these other functions may have on the device function-under-review, FDA will consider whether the other function(s) may impact the safety or effectiveness of the device function-under-review, by considering “whether there are shared computational resources, data dependencies, or any other type of relationship between the functions.” Id. at 9. If the other function(s) may impact the safety or effectiveness of the device function-under-review, FDA will consider whether there is an increased risk or adverse effect on performance.

Although sponsors may include information on other functions that positively impact the device function-under-review in their premarket submissions, FDA will only look for documentation on other functions in cases where the other function “could adversely impact the device function-under-review.” Id. at 11. A premarket submission for a multi-function device that includes other functions that could adversely impact the device function-under-review should include a description of the function, architecture and design information, risk analysis, requirements, and specifications. Also, FDA intends to include language in the submission summary (e.g., 510(k) summary) to indicate that “FDA assessed functions not subject to premarket review only insofar as they might adversely impact the safety and effectiveness of the functions subject to FDA premarket review.” Id. at 12.

This draft guidance should help those developing multiple function products to better understand how to limit their submissions to data and documentation for other functions only when they could adversely impact the device function-under-review. The boundaries have not always been clear in the past.

On the postmarket side, general control requirements are not applicable to non-device functions and will not be enforced for functions for which FDA does not intend to enforce applicable regulatory controls.

This area of device regulation has always been somewhat murky. The draft guidance is a positive step forward in providing clarity, even if it does not break new ground.

On April 27, 2018, Petitioners Breckenridge Pharmaceutical, Inc. and Nexgen Pharma, Inc. filed a Petition for Review in the United States Court of Appeals for the District of Columbia Circuit. The Petition seeks review of a final FDA order published in the Federal Register on April 2, 2018 (the “Order”). The Order denied requests for a hearing and withdrew approval for ANDAs for prescription polyethylene glycol 3350 (PEG-3350). The Order was initially effective May 2, 2018 but was stayed by FDA in response to several petitions for stay to the Agency. Currently, the Order goes into effect on November 2, 2018 – but FDA may not have the final say on this issue. Breckenridge/Nexgen’s asks the D.C. Circuit to set aside the Order as clearly erroneous, arbitrary and capricious, an abuse of discretion, and not supported by substantial evidence.

The Petition for Review is not a surprise. Breckenridge/Nexgen was one of several Rx ANDA holders participating in the Agency proceedings. Additionally, it and the other Rx ANDA holders had included in their petitions for stay to the Agency arguments that a stay was required to permit judicial review.

While FDA granted a stay until November 2, 2018, the Agency rejected the Rx ANDA holders arguments that a stay was required under 21 U.S.C. § 10.35 (e), because the criteria in (e)(1)-(4) were met.. Instead, FDA reasoned that the Agency petitioners had established that a stay was “in the public interest and in the interest of justice,” and therefore a discretionary stay was warranted—but not required. Breckenridge/Nexgen challenge both FDA’s Order and FDA’s stay determination.

Because a Petition for Review only starts the process for judicial review, it does not set forth the substance of the arguments that Breckenridge/Nexgen will make to the D.C. Circuit. That said, the Agency proceedings have been pending for some time, so the arguments are not unfamiliar to dedicated FDA Law Blog readers (indeed, we blogged on these issues here, here, and here). For those of you who need a refresher on the regulatory history of laxatives, here’s a quick recap: in April 2007, FDA approved an NDA for an Rx-to-OTC switch for MiraLax. Five ANDAs based on MiraLax as the RLD had already been approved, so FDA issued a letter to the ANDA holders explaining that FDA believes their prescription products, which bear the “Rx only” symbol, are misbranded and may not be lawfully marketed. To lawfully market PEG-3350, according to the FDA letter, the ANDA holders must file new ANDAs referencing the OTC version of MiraLax and update the labeling to OTC labeling. FDA published a Notice of Opportunity for a Hearing in the Federal Register on October 24, 2008 (73 Fed. Reg. 63491) proposing to withdraw approval of the prescription PEG 3350 ANDAs. Four ANDA holders submitted timely requests for a hearing and supporting evidence, but FDA denied a hearing in both its proposed order of May 2014 and its final order of April 2018.

In a joint Petition for Stay at the agency level, Breckenridge/Nexgen argued that the final order irreparably harms their business and should be vacated. They explain that there is a meaningful difference between the Rx and OTC versions of PEG-3350 – duration of use, as well as reimbursement – and raise procedural errors and misstatements during the administrative process. Because the Order refused to consider all information submitted in 2014 and did not address Breckenridge/Nexgen’s arguments regarding outstanding factual issues with respect the scope of the Rx-to-OTC switch, those arguments may very well be made before the D.C. Circuit. Two Rx ANDA holders also filed petitions for stay with the Agency. Our firm represented one of those Rx ANDA holders.

As of the writing of this post, no briefing schedule has been set. The court has set May 31, 2018 as the date for Petitioner’s  procedural motions.

USDA announced the publication of its much awaited proposed rule establishing a National Bioengineered Food Disclosure standard as mandated by Congress almost two years ago (for more on that law, see our prior posting here).  The rule is scheduled to publish in the Federal Register on May 4, but for those who can’t wait, it’s available in prepublication form.  We’ll follow up with a posting on key aspects of the proposed rule, but one thing bears emphasis now: the deadline for comments is July 3, 2018, and USDA has stated that the comment period will not be extended.  It therefore behooves those with an interest in the rule to make the timely submission of comments a top priority.

In 2015, Senators D. Feinstein, R. Durbin and K. Gillibrand asked GAO to investigate the U.S. Department of Agriculture’s (USDA’s) Food Safety and Inspection Service (FSIS) pathogen standards for meat and poultry products and identify any steps that FSIS could make to address food safety. On April 18, 2018, GAO published its report of the two year investigation, Food Safety: USDA Should Take Further Action to Reduce Pathogens in Meat and Poultry Products.

Though the U.S. food supply is considered safe, the Centers for Disease Control and Prevention estimates that foodborne pathogens cause about 9 million illnesses each year. Two million of the illnesses are associated with Salmonella and Campylobacter.

GAO recognized that FSIS has taken a number of actions to address food safety, but concluded that it can do some things better. Among other things, FSIS has established performance standards for Salmonella and Campylobacter for some meat and poultry products. These standards are used to reduce contamination in meat and poultry before the products are sold. FSIS began setting these standards in 1996. At that time, the standards were set at industry-wide prevalence levels, not at levels that may protect human health. Since then, FSIS has changed its procedures and developed more science-based performance standards.

Over time, FSIS developed performance standards for Salmonella on beef carcasses, ground beef, pork carcasses, chicken carcasses and parts, comminuted chicken, turkey carcasses, and comminuted turkey. FSIS also developed performance standards for Campylobacter on chicken carcasses and parts, comminuted chicken, turkey carcasses, and comminuted turkey. Although some of the standards such as the standards for chicken have been updated, the standards for pork carcasses, beef carcasses and ground beef have not been updated since 1996 and there are no time frames for updating them. Moreover, for some commonly consumed products, such as turkey breasts, ground pork and pork chops, FSIS has never set standards. It was not clear to GAO how FSIS decides for which products it sets standards and when it updates standards.

The GAO made two recommendations regarding the performance standards: (1) document the process for deciding which products are considered for new standards (so as to better ensure that such decisions will be risk-based), and (2) set time frames for determining which updates or standards are needed for ground beef, beef carcasses, pork cuts, and ground pork.

Although FSIS agreed with the recommendations, its response included some comments. For example, FSIS indicated that it made a risk-based decision to not develop performance standards for turkey breast. Salmonella levels in turkey carcasses are typically low and consumption of turkey is relatively low, such that there appears minor exposure to pathogens from turkey parts.

As part of the audit, GAO also examined steps FSIS has taken to address challenges in reducing pathogen levels in meat and poultry that were identified in a 2014 GAO report. In that report, GAO found that the level of pathogens in poultry products can be affected by practices on farms where poultry are raised. Even though FSIS has no authority over such farm practices, GAO recommended that FSIS issue guidelines on the effectiveness of practices for controlling Salmonella and Campylobacter on farms. In response, FSIS did in fact revise its guidelines to include information on the effectiveness of on-farm practices for controlling pathogens in poultry and beef cattle. The draft guidelines for controlling Salmonella in pigs, however, do not contain such information. GAO recommends that FSIS include such information in the final guidance.

Senators Feinstein, Durbin, and Gillibrand sent the GAO report with four of their own questions (about timing of new performance standards and other actions recommended actions by GAO as well as a question about use of whole genome sequencing) in a letter to Secretary of Agriculture Sonny Perdue.

FDA is continuing the crackdown on the sale of tobacco products to minors (see our post here regarding recent FDA actions). On May 1, 2018, FDA and FTC issued 13 joint warning letters to manufacturers, distributors, and retailers for misleadingly labeling or advertising nicotine-containing e-liquids as kid-friendly food products, such as juice boxes, candies, and cookies.

The Federal Food, Drug, and Cosmetic Act (FDCA) provides that a tobacco product shall be deemed misbranded if, in relevant part:

1) its labeling is false or misleading (section 903(a)(1)), or

2) if, in the case of any tobacco product distributed or offered for sale in any State, its advertising is false or misleading in any particular (section 903(a)(7)(A)) or it is sold or distributed in violation of certain regulations, such as regulations prohibiting sale to minors (section 903(a)(7)(B)).

Section 201(rr)(4) of the FDCA prohibits a tobacco product from being marketed in combination with any other article or product regulated under the FDCA (including a drug, biologic, food, cosmetic, medical device, or a dietary supplement).

In terms of FTC authority, Section 5 of the FTC Act prohibits unfair or deceptive acts or practices in or affecting commerce. This prohibition includes practices that present unwarranted health or safety risks.

FDA and FTC found that companies violated the provisions outlined above by using false or misleading labeling and/or advertising that cause e-liquids to imitate food products, particularly ones that are marketed toward and appeal to minors. The batch of 13 warning letters all cited violations to both misbranding violations (under section 903(a)(1) of the FDCA) and unfair or deceptive acts or practices (Section 5 of the FTC Act). In addition, 6 warning letters also cited a violation of section 903(a)(7)(B) of the FDCA for sale of e-liquid products to minors and 1 warning letter cited a violation of section 201(rr)(4) of the FDCA for marketing a tobacco product in combination with a food product.

The warning letters mention that children are at particular risk for ingesting e-liquid products when the products have labeling and/or advertising that cause the product to imitate food products typically marketed toward and appealing to children. The warning letters also make the point that children are at particular risk because exposure to nicotine in the e-liquid can result in acute toxicity and, further, that severe harm can occur, including seizure, coma, respiratory arrest, and death from cardiac arrest.

The issuance of this batch of warning letters is just the most recent part of FDA’s ongoing efforts to enforce regulations specifically aimed at addressing youth access to tobacco products. We anticipate more FDA actions in the future and will continue to provide updates.

On April 24, 2018, FDA released a statement regarding new enforcement actions and a Youth Tobacco Prevention Plan aimed to help stop minors from using e-cigarette products.

Under the Family Smoking Prevention and Tobacco Control Act (“Tobacco Control Act”), a “tobacco product” is defined as “any product made or derived from tobacco that is intended for human consumption, including any component, part, or accessory of a tobacco product.” The Tobacco Control Act gave FDA the express authority to regulate cigarettes, cigarette tobacco, roll-your-own tobacco, and smokeless tobacco. Any other “tobacco product” could be regulated by FDA only if the Agency issued regulations “deeming” such products to be subject to the Tobacco Control Act. As discussed in our previous post, on May 10, 2016, FDA published the final “deeming regulation” asserting authority over all tobacco products meeting the broad statutory definition of a “tobacco product.” This authority extends to electronic nicotine delivery systems (ENDS), which may be described with terms such as vapes, vaporizers, vape pens, hookah pens, e-cigarettes, or e-pipes. ENDS products typically use a liquid (“e-liquid”) that contains nicotine. This e-liquid is heated into an aerosol that can be inhaled by the user. ENDS products may be manufactured to look like traditional tobacco products or may resemble items such as pens or USB drives.

FDA cites the following CDC statistics regarding the use of ENDS products by minors:

• More than 2 million middle and high school students were current users of e-cigarettes in 2016
• 11% of high school and 4.3% of middle school students were current users of e-cigarettes in 2016
• E-cigarette use rose from 1.5% to 16.0% among high school students and from 0.6% to 5.3% among middle school students from 2011 to 2015

We have previously discussed FDA’s comprehensive plan for tobacco and nicotine regulation announced last July (here). FDA’s most recent enforcement activity is more narrowly focused on the use of ENDS products by minors, and singles out one ENDS product in particular. In its April 24 statement, FDA outlined a series of enforcement and regulatory steps.

First, FDA announced that on April 6, 2018 it initiated a large-scale, undercover, nationwide blitz that will continue until the end of April 2018. This blitz focuses on the sale of e-cigarettes (specifically products under the JUUL brand) to minors at both brick-and-mortar and online retailers. The Agency’s efforts have already revealed numerous violations according to the FDA. This blitz, in addition to other compliance checks, has resulted in FDA issuing 40 warning letters for the illegal sale of e-cigarettes, specifically JUUL products, to minors.

Second, FDA contacted eBay regarding several listings for JUUL products on the website. According to FDA, eBay removed the listings and voluntarily implemented measures to prevent against re-listing of the items. It is possible that other online retailers with e-cigarette products, specifically JUUL products, may receive similar communications from the Agency.

Third, on April 24, 2018, FDA sent an official request for information to JUUL Labs, requesting the company submit information, such as documents related to product marketing; research on the health, toxicological, behavioral or physiologic effects of the products, including youth initiation and use; whether certain product design features, ingredients or specifications appeal to different age groups; and youth-related adverse events and consumer complaints associated with the products. FDA is planning on sending additional letters to other manufacturers and has asserted that companies that do not comply will be in violation of the law and subject to enforcement.

Fourth, the Agency announced that it is planning to take enforcement actions against companies that are marketing products in a way that is misleading to minors.

Finally, FDA is also continuing its efforts on science-based campaigns to educate minors about the dangers of all tobacco products, including e-cigarettes.

FDA Commissioner Gottlieb makes clear the focus of the Agency is ENDS products marketed and sold to minors. For adults, FDA believes that ENDS products may offer a potentially lower risk alternative for adult smokers, providing them with access to nicotine without the additional risks associated with the combustion of tobacco. However, the Agency states the viability of ENDS products serving this purpose is undermined if they attract minors.

The steps outlined above are just the first of those the FDA plans to pursue as part of the Youth Tobacco Prevention Plan, and additional steps will be announced in the future. FDA’s message to all tobacco product manufacturers and retailers is clear: the Agency is watching closely.

On April 13, 2018, FDA issued the final guidance documents “Considerations for Design, Development, and Analytical Validation of Next Generation Sequencing (NGS) – Based In Vitro Diagnostics (IVDs) Intended to Aid in the Diagnosis of Suspected Germline Diseases” (hereinafter the NGS Guidance, available here) and “Use of Public Human Genetic Variant Databases to Support Clinical Validity for Genetic and Genomic-Based In Vitro Diagnostics” (hereinafter the Databases Guidance, available here). We previously blogged on the draft guidance documents issued in July 2016 here. As we discussed in our earlier post, these guidances have the possibility to be incredibly important to the IVD industry given the tremendous potential that sequencing holds.

The two guidances could hardly have undergone more different degrees of revision since their drafts were issued. The Databases Guidance received no substantive changes as compared to the draft. On the other hand, the NGS Guidance has undergone significant changes as compared to its draft, including its name. The draft NGS Guidance was originally named the “Use of Standards in FDA Regulatory Oversight of Next Generation Sequencing (NGS)-Based In Vitro Diagnostics (IVDs) Used for Diagnosing Germline Diseases.” NGS test developers will want to ensure they closely read the final NGS guidance to understand the full extent of its changes. Below we discuss several of the significant substantive changes to the NGS Guidance.

It is important to note that FDA provided no explanation for the changes to the NGS Guidance. Unlike the case with regulations, where FDA describes the reasons for revisions, guidances keep readers guessing as to why FDA’s thinking has shifted.

One of the major changes to the scope of the guidance is that it now applies only to NGS-based IVDs intended to diagnose suspected germline diseases in symptomatic patients. The guidance specifically states that it “does not address tests intended for use in the sequencing of healthy individuals.” The original guidance did not limit the scope of the guidance to only symptomatic individuals. This is an important change that will limit the scope and impact of the guidance to industry.

The guidance does, however, include several new helpful sections, including one regarding recommendations for reviewing changes to device design and production. This section pertains to all changes, including those that may or may not require premarket review. The guidance provides general guidance regarding assessing changes, including revalidation. The guidance also includes a new Appendix A. This appendix includes illustrative examples to aid in the guidance’s recommendations regarding analytical tests.

Finally, the NGS Guidance includes a notably shorter discussion of the possible exemption of NGS-based tests for germline diseases as compared to the draft. The draft had a full section regarding the possibility of an exemption for such tests. The final NGS Guidance still leaves open the potential for NGS-based tests being exempt from premarket notification. But, with a much more limited discussion in the final guidance it may be a signal that the Agency believes it is less likely that these tests will actually be exempt once classified. The guidance continues to state that it anticipates that the de novo pathway is the appropriate premarket pathway for these IVDs.

The extent of changes to the final NGS Guidance likely reflect that the Agency’s understanding and view regarding these tests is continuing to evolve. That will almost certainly remain the case for years to come. This is an area we will continue to watch closely and look forward to seeing FDA’s first de novo authorization for an NGS test to diagnose a germline disease.

In 2014, the Center for Science in the Public Interest (CSPI) filed a Citizen Petition requesting that FDA ban the retail distribution of highly concentrated caffeine marketed as a dietary supplement and specify limits on the forms in which caffeine may be sold.   On April 16, 2018, on the same day that FDA issued guidance regarding highly concentrated caffeine in dietary supplements, FDA denied the petition.

FDA denied the Petition because, as explained in the denial, the Agency does not think that the requested actions (involving rulemaking) are necessary. It points to the guidance and “publication of information directed toward industry and consumers, through which [FDA] communicated about the legal status of” highly concentrated caffeine products.

In the guidance, FDA explained that it generally considers products containing potentially lethal amounts of pure or highly concentrated caffeine in powder or liquid form sold in bulk to be adulterated under FDC Act § 402(f)(1)(A). As discussed in the guidance, FDA’s concern relates to the difficulty of separating out a safe amount (serving) of caffeine. FDA has taken the position that labeling the product with instructions at to a safe serving size and warning statements do not mitigate the risk; notwithstanding the provision of a warning, directions, and dosing cups or other tools, the highly concentrated bulk caffeine product continues to present a significant or unreasonable risk of illness or injury.

The guidance also provides some examples of caffeine products that, according to FDA, do not present a significant or unreasonable risk of illness or injury. Assuming that the product otherwise complies with all applicable legal requirements, FDA likely will not consider caffeine supplement in solid dosage form or premeasured packets or containers that do not provide an excessive amount (not defined) of caffeine per dosage form adulterated. Even though such products may be highly concentrated, the dosage form eliminates the need to measure the serving and thus avoids the risk of inaccurate dosing. To avoid an adulteration charge for bulk powdered or liquid caffeine product, the caffeine concentration must be low so that a serving error or misunderstanding about dosing would not normally be expected to lead to a toxic/life threatening situation.

In the Federal Register notice, FDA justified issuing the guidance as final guidance; according to the Agency, the threat to public health posed by pure and highly concentrated caffeine products made prior public participation not feasible.

It is reasonable to expect that the Guidance will have the effect of discouraging the marketing of highly concentrated caffeine products sold in bulk form. Thus, it appears that even though FDA denied the Petition, CSPI effectively got what it requested and the Agency avoided having to go through notice and comment rulemaking.

Earlier this month, FDA issued a draft guidance: Expansion of the Abbreviated 510(k) Program: Demonstrating Substantial Equivalence through Performance Criteria. This draft guidance would expand use of the Abbreviated 510(k) pathway as follows: “The intent of the guidance is to describe an optional pathway for certain, well understood device types, where a submitter would demonstrate that a new device meets FDA-identified performance criteria to demonstrate that the device is as safe and effective as a legally marketed device.” Id. at 2.

The current Abbreviated 510(k) program allows a sponsor to demonstrate some of the performance characteristics necessary to support a finding of substantial equivalence by showing conformity to FDA-recognized consensus standards. In this guidance, FDA acknowledges that the current substantial equivalence analysis, which requires direct comparison testing can sometimes be very burdensome. For example, it is difficult to conduct comparison testing when a predicate device is not marketed or where it is prohibitively expensive. Another example is a device that relies on multiple predicate devices for different performance and technological characteristics may be required to conduct multiple comparative tests.

The draft guidance proposes an Expanded Abbreviated 510(k) program, in which sponsors would be able to utilize the same mechanisms available in the current Abbreviated 510(k) program to allow a demonstration of all performance characteristics. In some circumstances, no direct comparison testing would be required. A predicate device would still be identified, but testing of the proposed device would be conducted against objective performance criteria.

FDA plans to issue guidance documents to establish such performance criteria and identify the types of eligible devices. This guidance may include identification of products by product code, appropriate intended uses, appropriate indications for use, and expectations for technological characteristics.

This initiative should be considered a modest, but useful, tweak to the 510(k) program. While it may eventually ease testing burdens on well‑understood device types, FDA may require some time to issue a full panapoly of product-specific guidances. We suspect, though, that FDA has some devices in mind that it will address relatively quickly. Most device types will likely not be eligible for the program.

Anyone interested in submitting comments on the draft guidance must do so by July 11, 2018.

On April 12, 2018, the three FDA Centers jointly issued the draft guidance, “Investigational In Vitro Diagnostics in Oncology Trials: Streamlined Submission Process for Study Risk Determination” (draft available here). The draft guidance outlines a process for obtaining FDA’s feedback regarding whether an investigational IVD requires an approved Investigational Device Exemption (IDE) when used in the study of an Oncology therapeutic product. As we discussed in our earlier post (here), FDA’s December draft guidance regarding investigational IVDs includes an expansive definition, indicating that IVDs used in therapeutic product studies must be either investigational or cleared/approved. Thus, this guidance would apply to IVDs that are investigational or those that are currently marketed for non-diagnostic use (e.g., research use only).

The majority of IVD investigations have historically been exempt from the IVD studies pursuant to 21 C.F.R. § 812.2(c)(3). IVD investigations are exempt if the IVD is appropriately labeled as investigational pursuant to 21 C.F.R. Part 809, and it:

(i) Is noninvasive,

(ii) Does not require an invasive sampling procedure that presents significant risk,

(iii) Does not by design or intention introduce energy into a subject, and

(iv) Is not used as a diagnostic procedure without confirmation of the diagnosis by another, medically established diagnostic product or procedure.

Id. § 812.2(c)(3). FDA issued guidance regarding interpretation of these four criteria in 2010 (available here). The 2010 guidance does not, however, cover all possible IDE exemptions nor does it discuss when/if a companion diagnostic fits within the above criteria. In recent years, investigational IVDs used in therapeutic product clinical studies where the IVD will ultimately be a companion diagnostic have not been exempt from the IDE requirements.

Prior to issuance of the draft streamlined oncology study risk determination guidance, study sponsors could seek a determination from CDRH as to whether an IDE was required for an investigational IVD by submitting a study risk determination pre-submission. The new draft guidance indicates that oncology therapeutic study sponsors can now request this feedback via FDA Form 1571 when it submits an Investigation New Drug (IND) application. CDER or CBER will seek input from CDRH in providing its feedback. The guidance states that sponsors should include the following information on their form when seeking FDA feedback regarding the IDE requirements applicable to IVDs used in the planned study:

• How the results from the investigational IVD will be applied in the clinical trial;
• What is known about the prevalence of the biomarker (evaluated by the investigational IVD) in the patient population; and
• The specimen type that will be collected for investigational IVD testing (including the anatomical site) and whether any biopsy required for investigational IVD testing could present a potential for serious risk to the health, safety, or welfare of the subject.

With regard to the third bullet, FDA notes that this process does not apply “if an invasive biopsy that presents a potential for serious risk to health, safety, or welfare of the subject is required for investigational IVD testing for enrollment.” The guidance appears to suggest that such invasive biopsies automatically require an IDE, a position which would be consistent with § 812.2(c)(3)(ii).

The guidance explains that FDA will provide its feedback regarding whether an investigational IVD requires an IDE in a “May Proceed Letter.” This timing seems appropriate if an IDE is not required. However, if an IDE is required, it would not seem ideal for the drug or device sponsor to need to begin the IDE approval process after the IND has already been approved. Thus, this process seems as though it may be helpful for therapeutic and IVD manufacturers when the sponsor is seeking – and obtains – confirmation that the investigational IVD is exempt from the IDE requirements. In addition, depending on the parties’ (IVD manufacturer and therapeutic manufacturer) relationship, it may be challenging for only the therapeutic sponsor to communicate with FDA via the IND application regarding the proposed diagnostic test.

In our view, this process may be modestly helpful; however, it only addresses part of the IVD-therapeutic product question. The often more important question is whether FDA will view the IVD as a companion diagnostic. The draft guidance doesn’t touch that topic. In order to be truly helpful to study sponsors, we suggest that FDA expand the proposed program to also allow study sponsors to seek a determination as to whether the IVD will be viewed as a companion diagnostic. It is important to note that largely similar information required for the study risk determination also apply when assessing whether an IVD is a companion diagnostic.

Last week United States ex rel. Campie v. Gilead Sciences Inc. took one step closer to being the first FCA materiality case to be taken up by the Supreme Court since the Court’s seminal decision in Universal Health Services, Inc. v. United States ex rel. Escobar – or one step further away, if you read the tea leaves a different way. On April 16, the Supreme Court invited the U.S. Solicitor general to “file a brief. . . expressing the views of the United States” on Gilead’s petition for writ of certiorari.   It is not unusual for the Court to call for the views of the Solicitor General in a case where the United States is not a party (the United States declined to intervene in Gilead), but the government has a significant interest in the case. When the Supreme Court does call for the Solicitor General’s views on a petition for cert, it often acts in accordance with the Solicitor General’s recommendations (with respect to whether to grant certiorari, not necessarily with respect to the merits of the case).

We previously blogged about the Gilead case here, here, and here. Importantly, the Ninth Circuit’s decision Gilead is an outlier among the Circuits’ various interpretations of Escobar.  In its Gilead decision, the Ninth Circuit arguably seeks to either reverse or ignore Escobar’s emphasis on a rigorous standard for FCA materiality. For readers of this blog, in particular, Gilead is significant; the Ninth Circuit’s reasoning would allow FCA cases to proceed based on FDA regulatory infractions, because the government would have the option not to pay a claim based on the noncompliance—and even if FDA’s response to the infractions indicated that it did not view the regulatory issue as material. Gilead and several amici have urged the Supreme Court to take up the case, in part to avoid undermining FDA’s regulatory authority.

The Supreme Court may be inclined to grant certiorari in Gilead to address the Ninth Circuit’s misreading of Escobar and the FCA materiality standard. Escobar was decided by a unanimous Court in June 2016, and since then the Court’s composition has remained the same except for the addition of Justice Neil Gorsuch. The Court’s request for the Solicitor General’s views also suggests that the Court is willing to take up the Gilead case. But it seems too much to hope that the Solicitor General would recommend a course of action that could make it more difficult for the federal government to recover monies under the FCA, even if the government would welcome a case that revisits Escobar to clarify and/or limit that case’s materiality language. In fact, the government has previously expressed views on FCA materiality under Escobar that are similar to those expressed by the Ninth Circuit in Gilead. See, e.g., Statement of Interest of the United States, United States ex rel. Kolchinsky v. Moody’s Corp., 12-cv-1399 (S.D.N.Y May 8, 2017). The Solicitor General often takes months to file its brief in response a Supreme Court request, so we may have to wait some time to find out exactly what the government has to say.

Separately, on the same day that the Supreme Court made its request in Gilead, it announced the decision to deny certiorari in another significant FCA case, United States ex rel. Nargol v. DePuy Orthopeadics, Inc., relating to the pleading standards for an FCA case under Fed. R. Civ. P. 9(b). Justice Alito did not participate in the decision to deny cert. The Supreme Court’s denial in DePuy leaves in place a First Circuit ruling we blogged about here and here, which applied a relaxed pleading standard to a False Claims Act complaint that alleged indirect submission of false claims. The First Circuit took the position that it was possible for a plaintiff to adequately plead against defendant based on a statistical certainty that false claims were submitted as a result of the defendant’s alleged actions, rather than alleging the specifics of any actual false claims. This decision leaves defendants guessing about the courts’ application of 9(b) to indirect false claim cases, because the Circuits apply divergent pleading standards with respect to the use of statistics to establish the existence of false claims.

As we previously reported, the United States Cattlemen’s Association (USCA) filed a Petition with the Food Safety and Inspection Service (FSIS), asking that FSIS establish formal definitions of “meat” and “beef” that exclude what petitioners call lab grown meat and products prepared from plant or insect protein. Until April 17, the majority of comments submitted have been in support of the petition.

The National Cattlemen’s Beef Association, (NCBA), however, does not support the Petition. As described in its comment to the Petition, the NCBA does not believe that the action requested by USCA “will adequately provide meaningful protection for beef nomenclature.”  In contrast to the USCA, the NCBA wants FSIS to assert jurisdiction over foods produced from cell or tissue culture that are derived from livestock and poultry animals or their parts, so as to ensure a level playing field. NCBA takes the position that, since cell-cultured or lab-grown meat products are derived from parts of a carcass, in this case stem cells, these products fall squarely within the definition of meat food product.  Even if this were not the case, NCBA believes that “FSIS should assert jurisdiction as a means of ensuring regulatory equity.”

As to the labeling of the product, NCBA seems of two minds. It asserts that the cultured meat should not be permitted to be marketed as beef. Yet, it argues that, if the producers of lab-grown or cultured meat products wish to call these products meat, they must adhere to the same food safety inspection standards and comply with the same labeling standards as traditional meat food products; only in that way can “arbitrary marketing claims,” such as “clean meat,” be avoided.

As far as products that clearly fall outside USDA’s jurisdiction are concerned, such as products made from insects or plants, or other non-animal products, NCBA suggests that FSIS ask FDA to take appropriate and immediate enforcement action against allegedly mislabeled imitation beef products.

In a joint comment, the Good Food Institute, Field Roast Grain Meat Co., Finless Foods, Hungry Planet, Impossible Foods, Lightlife, Sweet Earth Enlightened Foods and the Tofurky Company (collectively GFI) also oppose the USCA Petition. GFI’s comments focus primarily on plant-based products.  GFI argues that FSIS lacks authority over the labeling of such products, and that any restriction to the truthful use of the terms “meat” or “beef” with appropriate qualifiers that accurately disclose the nature of the plant-based product would violate the First Amendment.

As far as cultured meat is concerned, GFI’s comments suggest that it believes that these products may be under FSIS jurisdiction. Referring to dictionary definitions for “meat,” GFI argues that meat does not require slaughter.  In a footnote, GFI requests that FSIS work closely with what it calls “clean meat companies” to determine the appropriate labeling for these products.  GFI opposes USCA’s request to limit the definition of beef to meat that comes from cattle “that have been raised and harvested in the traditional manner.”  GFI contends that FSIS does not have the authority to “prop up an industry or favor one production method over another,” and that such narrowing of the definition would inhibit innovation across the industry.  Moreover, GFI points out that what is traditional is subject to interpretation; arguably, current methods of cattle production are not traditional.

On April 13, FSIS announced that it was extending the comment period for the petition (which was set to close on April 17) by another 30 days. Comments submitted after April 13 are posted on regulations.gov.

Meanwhile, in a March 28, 2018 letter to GAO, U.S. Rep. Rosa DeLauro, D-CT requested that GAO “investigate what regulatory framework, if any exists for cell-cultured food products and how this framework compares to other international approaches,” e.g., those in Canada, Japan, and the European Union. According to the request, such information is needed for Congress to address this emerging issue and ensure that it is “properly overseen by the relevant . . . agencies” once these types of products becomes commercially available.

Declaring its intent to stand on the original complaint in FTC v. Shire ViroPharma, the FTC has appealed the District Court for the District of Delaware’s decision to dismiss the Commission’s unfair competition case against Shire without prejudice.  We previously blogged about this case here, and here.

Although District Court dismissals without prejudice are typically not subject to immediate appeal, the FTC seeks appellate jurisdiction by declaring that it will not amend its original Complaint despite the District Court’s grant of leave to do just that.  Rather, the FTC will risk abandoning its case in District Court in favor of seeking a review of the key legal issue by the Third Circuit. This speaks to the significance of the lower court’s ruling that the FTC had failed to meet its statutory burden in bringing the case – the Shire ruling has already been cited against the FTC in at least four other pending cases.

We will continue to follow this case as it develops.